Renal carcinoma CD105−/CD44− cells display stem-like properties in vitro and form aggressive tumors in vivo

Abstract

clear cell renal cell carcinoma (ccRcc) is the most common kidney cancer. prognosis for ccRcc is generally poor since it is largely resistant to chemo-and radiotherapy. Many studies suggested that cancer stem cells/tumor initiating cells (CSCs/TICs) are responsible for development of tumor, disease progression, aggressiveness, metastasis and drug resistance. However, tumorigenic potential of CSCs/ tics isolated from established Rcc cell lines-basic ccRcc research model-has never been investigated in vivo. CD105+, CD105−, CD44+ and CD44− as well as CD44−/CD105− CD44+/CD105+ and CD44−/ CD105+ cells were isolated from Caki-1 RCC cell line, confirming coexistence of multiple subpopulations of stem-related phenotype in stable cell line. Sorted cells were injected subcutaneously into noD SciD mice and tumor growth was monitored with MRi and pet/ct. tumor growth was observed after implantation of CD105+, CD44+, CD44−, CD44−/CD105+ and CD44−/CD105− but not CD105− or CD44+/CD105+. Implantation of CD44−/CD105− cells induced tumors that were characterized by longer T1 and distinct metabolic pattern than other tumors. All the tumors were characterized by low uptake of [18F]FDG. CD105+ and CD44− tumors expresses Nanog and Oct-4, while CD44− tumors additionally expressed endothelial cell marker-CD31. Renal cell carcinoma (RCC), is the 10th malignancy worldwide and the most frequent type of kidney cancer in adults. Each year in Europe approximately 88 400 patients are diagnosed with RCC; the incidence and mortality of RCC are rising at a rate of 2-3% per decade, therefore novel therapies directed against RCC are needed. At the same time despite advancements in diagnostic techniques, up to 30% of newly diagnosed patients already present with metastases, and a large portion of patients that undergo surgical treatment experience the RCC recurrence, therefore drugs targeted against metastasis initiating cells would be of great interest in the future 1,2. Cancer stem cells (CSCs) are characterized by the potential to self-renew, high tumorigenicity in nude mice and the ability to efficiently reconstitute all tumor subpopulations and primary tumor phenotype 3-5. CSCs are also responsible not only for cancer development, but also for disease recurrence, progression and metastatic spread, together with cancer aggressiveness, including treatment resistance such as chemo/radiotherapy, and targeted treatment 6,7 , therefore basic research with careful model selection to understand their biology is mandatory to define novel potential therapeutic targets for all RCC subtypes 8,9 .

Identification of a novel cancer stem cell subpopulation that promotes progression of human fatal renal cell carcinoma by single-cell RNA-seq analysis

“…S4A-C). The well-known clear cell renal cell carcinoma (CCRCC) CSC markers (ALDH1A1, CD44, CXCR4, DCLK1, CD105, ITGB1, NT5E, PIK3R1, PROM1 and THY1) [20][21][22][23][24][25][26][27] were displayed in the featurePlot to verify the expression in the identified CDRCCCSC cluster ( Supplementary Fig S5A, B). It was found that ALDH1A1, DCLK1, ITGB1 and PIK3R1 were also expressed in the identified CDRCC CSC cluster.…”

The effect and molecular mechanism of hypoxia on proliferation and apoptosis of CD133+ renal stem cells

“…These findings are consistent with the biological features of stem cells such as that they secrete multiple cytokines and regulate diverse immune cells [ 8 , 9 ]. Some reports indicated renal stem cells express mesenchymal and embryonic stem cell markers, namely octamer-binding transcription factor 4 (Oct-4) and paired box gene 2 (PAX2) in mouse renal tubules [ 10 , 11 ]. Cluster of differentiation (CD)24 and CD133 can also be expressed in the embryonic kidney [ 12 ].…”

Heterogenous expression of endoglin marks advanced renal cancer with distinct tumor microenvironment fitness

“…20,30 However, a recent study that used the Caki-1 cells derived from skin metastasis of ccRCC indicated that CD44 -/ENGcells enriched CSCs. 31 In this study, CSCs had high tumorigenicity with distinctive angiogenic and metabolic characteristics in subcutaneous models. Therefore, we examined the tumorigenicity in several microenvironments, including in the kidney, and verified whether endoglin serves as a marker for CSC/CICs in ccRCC, using parental ccRCC cells OS-RC-2 and their derivatives.…”

“… 34 A previous study reported that ENG – /CD44 – renal cancer cells displayed a distinctive capability to induce angiogenesis. 31 The interference of endothelial signaling may have resulted in the failure in angiogenesis and the lower tumorigenic capability of ENG + cells in subcutaneous inoculation model compared with colony formation in vitro, in which angiogenesis is not needed.…”